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Oxidative Stress and Antioxidant Therapy in Cystic Fibrosis

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Oxidative Stress and Antioxidant Therapy in Cystic Fibrosis Biochimica et Biophysica Acta 1822 (2012) 690–713 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Review Oxidative stress and antioxidant therapy in cystic fibrosis☆,☆☆ Francesco Galli a,⁎, Andrea Battistoni b, Roberto Gambari c, Alfonso Pompella d, Alessandra Bragonzi e, Francesca Pilolli a, Luigi Iuliano f, Marta Piroddi a, Maria Cristina Dechecchi g, Giulio Cabrini g a Department of Internal Medicine, Laboratory of Clinical Biochemistry and Nutrition, University of Perugia, Italy b Department of Biology, University of Rome Tor Vergata, Italy c Department of Biochemistry and Molecular Biology, University of Ferrara, Italy d Dept. of Experimental Pathology & BMIE University of Pisa Medical School, Pisa, Italy e Infections and cystic fibrosis unit, San Raffaele Scientific Institute, Milan, Italy f Department of Medico-Surgical Sciences and Biotechnology, Vascular Biology & Mass Spectrometry Lab, Sapienza University of Rome, Italy g Laboratory of Molecular Pathology, Department of Pathology and Diagnostics, University Hospital of Verona, Italy article info abstract Article history: Cystic fibrosis is a lethal autosomal recessive condition caused by a defect of the transmembrane conductance Received 20 October 2011 regulator gene that has a key role in cell homeostasis. A dysfunctional cystic fibrosis transmembrane conduc- Received in revised form 16 December 2011 tance regulator impairs the efflux of cell anions such as chloride and bicarbonate, and also that of other solutes Accepted 17 December 2011 such as reduced glutathione. This defect produces an increased viscosity of secretions together with other met- Available online 28 December 2011 abolic defects of epithelia that ultimately promote the obstruction and fibrosis of organs. Recurrent pulmonary infections and respiratory dysfunction are main clinical consequences of these pathogenetic events, followed by Keywords: fi Cystic fibrosis pancreatic and liver insuf ciency, diabetes, protein-energy malnutrition, etc. This complex comorbidity is asso- Antioxidant ciated with the extensive injury of different biomolecular targets by reactive oxygen species, which is the bio- Oxidative stress chemical hallmark of oxidative stress. These biological lesions are particularly pronounced in the lung, in which Reactive oxygen species the extent of oxidative markers parallels that of inflammatory markers between chronic events and acute exac- Inflammation erbations along the progression of the disease. Herein, an abnormal flux of reactive oxygen species is present by Glutathione the sustained activation of neutrophils and other cystic fibrosis-derived defects in the homeostatic processes of pulmonary epithelia and lining fluids. A sub-optimal antioxidant protection is believed to represent a main con- tributor to oxidative stress and to the poor control of immuno-inflammatory pathways in these patients. Ob- served defects include an impaired reduced glutathione metabolism and lowered intake and absorption of fat-soluble antioxidants (vitamin E, carotenoids, coenzyme Q-10, some polyunsaturated fatty acids, etc.) and oligoelements (such as Se, Cu and Zn) that are involved in reactive oxygen species detoxification by means of enzymatic defenses. Oral supplements and aerosolized formulations of thiols have been used in the antioxidant therapy of this inherited disease with the main aim of reducing the extent of oxidative lesions and the rate of lung deterioration. Despite positive effects on laboratory end points, poor evidence was obtained on the side of clinical outcome so far. These aspects examined in this critical review of the literature clearly suggest that fur- ther and more rigorous trials are needed together with new generations of pharmacological tools to a more ef- fective antioxidant and anti-inflammatory therapy of cystic fibrosis patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. © 2012 Elsevier B.V. All rights reserved. 1. Introduction in the apical membrane of epithelial cells that line mucous mem- branes and submucosal glands [1]. Several mutations have been Cystic fibrosis (CF) is a lethal autosomal recessive disorder caused identified to cause this gene defect with the Phe508del, or ΔF508, by a single gene defect. This was identified in 1989 to map on the as one of the most common mutations in Caucasians. The prevalence chromosome 7 and to correspond to the gene coding for the trans- at birth varies in the different regions according with ethnic back- membrane conductance regulator (CFTR) that is mainly expressed ground, from roughly 1 in 3000 white Americans and northern ☆ This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. ☆☆ For the “Working Group on Inflammation in Cystic Fibrosis” of the Italian Society for Cystic Fibrosis and the Italian Cystic Fibrosis Research Foundation. ⁎ Corresponding author. E-mail addresses: [email protected] (F. Galli), [email protected] (A. Battistoni), [email protected] (R. Gambari), [email protected] (A. Pompella), [email protected] (A. Bragonzi), [email protected] (F. Pilolli), [email protected] (L. Iuliano), [email protected] (M. Piroddi), [email protected] (M.C. Dechecchi), [email protected] (G. Cabrini). 0925-4439/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.bbadis.2011.12.012 F. Galli et al. / Biochimica et Biophysica Acta 1822 (2012) 690–713 691 Europeans to 1 in 350,000 in Japan. Mutations are grouped in 6 clas- conspire with further mechanisms to worsen the prognosis of this ses based on the type of defect caused on CFTR protein metabolism inherited disorder (recently reviewed in [10]). and function. Several physiological processes affected by these muta- In view of these aspects, the CF patient is assumed to have a higher tions are related to the role of CFTR as anion channel. This mainly antioxidant demand. This has provided the rationale for the systematic regulates chloride efflux, but other and larger anions such as reduced investigation of antioxidant levels in blood and targeted tissues of CF glutathione cross the plasmalemma throughout this transmembrane patients, mainly the epithelium and lining fluids of the airways, and protein widely expressed in diverse epithelial tissues. Other ion to plan for antioxidant interventions that might rescue specificdefects transport systems are under its influence, such as bicarbonate of these patients. These also include the use of anti-inflammatory anion and sodium channels, so that a defective CFTR can impair agents and nutritional formulations which can produce an “antioxi- several processes such as cell volume and pH regulation, transepithe- dant effect”, i.e. the lowering of oxidative stress indices, as a result of lial transport, membrane conductance, and the GSH-related antioxi- their direct or indirect action. Despite a number of promising in vitro dant and detoxification activity in the extracellular milieu [2,3]. and pre-clinical observations, antioxidants used as oral supplements CFTR dysfunction is associated with an altered fluid and electrolyte or directly administered in the CF airways have failed to provide con- composition of secretions, their increased viscosity and progressive vincing evidence at the clinical level. Future efforts are required to iden- obstruction and fibrosis of organs [4]. The severity of these CF symp- tify more advanced agents and therapeutic strategies that may enhance toms varies independently of the type and number of mutations secondary prevention and chemotherapy of airway inflammation and diagnosed, suggesting that CFTR gene and its mutations interact oxidative stress in CF patients. Advances in the approaches capable of with other genes at the transcriptional and post-translational level improving nutritional status and antimicrobial therapy are of main to influence a wide series of physiological processes. Lung, pancreas relevance to further ameliorate quality of life and survival rates in CF. and liver are severely affected by these events, and recurrent infec- These aspects will be discussed in this manuscript with the aim of tions of the airways together with pancreatic insufficiency and diabe- providing an updated review of the literature as well as of strategies tes are most common conditions secondary to CF [1]. and future directions of antioxidant therapies in CF patients. The presence of a defective CFTR appears to produce a redox im- balance in epithelial cells and extracellular fluids and to cause an ab- 2. Inflammatory pathways and oxidative stress in CF normal generation of reactive oxygen species (ROS). A constitutive defect of GSH metabolism together with a lowered intake and absorp- 2.1. Progressive inflammatory damage in CF lungs and the contribution tion of fat-soluble antioxidant vitamins (vitamin E and carotenoids) of oxidants could contribute to a defective antioxidant protection, which is be- lieved to exacerbate oxidative stress indices along with the progres- Evidence supporting the occurrence of oxidative stress in CF is by sion of clinical status [5–7]. The development of inflammatory and now established and extensive [6,10–12]. As introduced above, CF- degenerative lesions in target tissues such as lung, pancreas and related defects of the pulmonary epithelium and a sustained PMN liver further exacerbate the shift from normal to abnormal flux of activation
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